Serum Rheology and Viscosity


Douglas Lobay, BSc, ND

Alice was a slim, spry, and ageless, elderly English lady who visited our clinic with some vague, innocuous complaints. After drawing her blood to do some general lab tests, letting the tube sit for 15 minutes and then spinning in a centrifuge for 10 minutes, I removed the tube to decant the serum sample. The lightly yellow-colored serum sample was amazingly crystal clear. She had an impeccably healthy diet and her only bad vice was her daily tea with sugar and a sweetened scone. I believed her serum sample directly reflected the internal state of her clean blood rheology and viscosity.    

As a naturopathic doctor who draws blood and sends serum samples to different labs throughout North America for different and unique tests, I have observed an interesting phenomenon after spinning the serum separator tubes (SSTs) in preparation of transport. After following the same procedure, I have seen different levels of serum viscosity after centrifuging. Some patients have serum that is thicker than others and this generally corresponds to their level of lipids, particularly triglycerides or other coagulable factors. While it is easy to lose your focus in the abstraction of lab values, a relatively easy and simple evaluation of blood viscosity might be just looking at serum thickness.

Most people would innately recognize that thick blood does not flow that well. Many of the diseases of aging, including atherosclerosis, cardiovascular disease, and cancer predispose to thick blood and blood clots. Keeping the blood “thinner” and “flowing” would be a beneficial strategy to prevent these diseases and promote longevity.

Rheology is the term used to describe the flow dynamics of a fluid like blood. Viscosity refers to the thickness of a fluid like blood. Serum and plasma are the liquid constituents of blood that remain after the cellular products, namely white and red blood cells have been removed. Serum is that liquid portion that has specific clotting proteins removed, and plasma still has the clotting proteins.  A deformity in the shape of red blood cells or an increase in the number of red blood cells also contributes to an increase in the flow and thickness of blood. However, this paper will focus on the non-cellular components that contribute to serum rheology and viscosity.

Blood rheology and viscosity are determined by many factors, including the levels and oxidative status of lipids like cholesterol and triglycerides, high levels of simple sugars like monosaccharides and disaccharides, chronic infection or inflammation, high blood pressure, myocardial electro-physiology abnormalities like atrial fibrillation, exposure to endothelial toxins like cigarette smoke, inactivity and sedentary lifestyle, obesity, and intake of drugs, including specific hormones like estrogen and non-steroidal anti-inflammatory drugs like ibuprofen and naproxen.

Platelets are biconcave membrane-bound discs derived from megakaryocytes in bone marrow. The two major functions of platelets are for hemostasis to help stop bleeding and help the innate and adaptive immune system. They are 2 to 3 micrometers in diameter and lack a nucleus. They are rich in vacuoles containing vasoactive chemicals, glycoproteins involved in cellular adhesion, endoplasmic reticulum required to produce cytokines like thromboxane A2, and microtubules. Bone marrow produces approximately 100 billion platelets per day. The average life of a platelet is between 8 and 9 days, whereupon they are broken down in the liver and spleen. There are between 150,000 and 400,000 platelets per millimeter of blood or 150 to 400 billion per liter of blood.

When a blood vessel is damaged from injury the delicate inner endothelial lining releases a variety of cytokines that attract platelets to the site of injury. Upon exposure of platelets to the damaged endothelial collagen, platelets change shape, aggregate at the site of injury, adhere to the lining, stick to other platelets and release more cytokines that promote cellular adhesion, aggregation, and initiate the protein-clotting cascade.

During inflammation that occurs at the site of endothelial injury, arachidonic acid is converted to a variety of cytokines, including thromboxane A2 by the enzyme cyclo-oxygenase. Thromboxane A2 promotes platelet aggregation and vasoconstriction. Platelets also contain cyclo-oxygenase that produces thromboxane and other cytokines that promote aggregation, adhesion, and the protein clotting cascade.

Drugs like acetyl salicylic acid (ASA) bind to the cyclo-oxygenase active binding site and directly inhibit the production of pro-inflammatory cytokines that cause platelet adhesion, blood clot formation, and vasoconstriction. Plavix (Clopidogrel) and Ticlid (Ticlodipine) inhibits adenosine diphosphate (ADP) binding to the platelet receptor that promotes platelet adhesion and aggregation.

Blood clotting or coagulation is the internal process by which blood turns from a liquid to semi-solid gel or mass after tissue injury or inflammation in a conserved effort to stop bleeding or hemorrhage and protect from further tissue damage. The two main factors involved in coagulation are platelets and blood proteins. Localized vasoconstriction at the site of injury also occurs limiting blood flow and further bleeding. The clotting cascade simultaneously occurs and includes a series of enzyme reactions involving proteins that ultimately leads to the formation of a fibrin clot at the site of injury. Fibrin is a non-globular strand of protein that forms a mesh framework for platelets, calcium, and other factors involved in blood clot formation.

The clotting cascade involves a series of continuous stepwise reactions with different proteins that catalyze an inactive protein precursor to an active enzyme. Thirteen proteins have been identified and are involved in a cascade of enzymatic reactions. The proteins are named numerically from Roman numeral I to XIII by their order of occurrence in the clotting cascade.

An inactive protein zymogen is activated by endothelial damage. The active enzyme then catalyzes another inactive protein into an active enzyme then so on in a stepwise series of reactions. The process culminates when prothrombin is converted into thrombin which then catalyzes the conversion of fibrinogen to fibrin which then forms the framework for blood clot formation.

Two different pathways of the coagulation cascade have been further identified; one is the intrinsic pathway, and one is the extrinsic pathway. They were considered equal in importance but ultimately the extrinsic pathway has proven to be more dominant. The intrinsic pathway as its name suggests occurs within blood vessels without overt tissue damage. It is important for coagulation when there is an infection or disseminated intravascular coagulation (DIC). Surface contact with a foreign substance can trigger a clotting cascade that involves protein factors XII, XI, X, IX and VIII that then triggers a final common pathway with the extrinsic pathway.

The extrinsic pathway as its name suggests occurs when there is exposure of proteins to external tissue damage that then initiates a series of reactions. In this pathway activated factor VII catalyzes factor X which then catalyzes prothrombin to thrombin which further catalyzes fibrinogen to fibrin. The final common pathway is common to both the intrinsic and extrinsic pathways and involves factor X, prothrombin, thrombin, fibrinogen and fibrin. Factors III, IV and V are also involved in the final common pathway. Other cofactors involved in blood clotting include calcium, vitamin K, factor XIII, von Willebrand factor, kallikrein, and other chemicals.

Drugs like warfarin interrupt the vitamin K dependent clotting pathways thereby disrupting the clotting cascade and preventing proper fibrin formation. Newer direct-acting oral anticoagulants (DOACs) interrupt activation of factor X thereby disrupting the final common pathway and formation of a fibrin clot. These newer non-vitamin K dependent factor X blockers include apixabin (Eliquis), rivaroxaban (Xarelto) and dabigatran (Pradaxa). Fairly constant absorption profiles, distribution and breakdown pathways to a fixed dose of DOACs negate the necessity for  rigid coagulation monitoring.

There are many “natural” substances that also have anti-platelet and anti-coagulant properties and may be beneficial in keeping the blood thin and flowing easily.

Nattokinase is proteolytic enzyme isolated from a fermented cheese-like substance called natto that has been used in Asian cultures like Japan for two thousand years. It is produced by action of Bacillus subtilis bacteria on degrading soybeans. Nattokinase is the most predominant enzyme produced from this action and has demonstrated promising fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid-lowering, antiplatelet, and neuroprotective effects.  Nattokinase itself is a 270 amino acid chain that displays broad proteolytic activity. Its method of action is multi-factorial. It is a direct acting serine protease in its active enzyme binding site.  It not only degrades fibrin directly but also increases tissue plasminogen activator (tpa) and increases urokinase enzyme activity.

Nattokinase blocks pro-inflammatory and platelet aggregating cytokines like thromboxane. Nattokinase has demonstrated atherosclerotic plaque dissolving activity in vitro, in animal models and in human subjects. Decreased levels of clotting cascade proteins, including factor VII and factor VIII have been observed. Nattokinase has an excellent safety profile, but its concomitant use with other anticoagulant and anti-platelets drugs and supplements should be cautioned.1,2,3,4

Serratiopeptidase or serrapeptase is a proteolytic enzyme originally isolated from silkworm moths. It was first used in Japan in 1957. It has been widely used as a systemic anti-inflammatory and analgesic throughout the body. It is also produced by recombinant methods in Serratia bacteria species. Serrapeptase itself is a large 470 amino acid-long, zinc-containing metalloprotease enzyme that displays broad proteolytic activity. Its method of action is multifactorial. It is a direct-acting serine protease in its active enzyme binding site. It has been demonstrated to inhibit both cyclooxygenase COX-1 and COX-2 proinflammatory enzyme pathways. It also decreases inflammatory cytokines, including interleukin-6, bradykinin, and histamine. It has direct-acting fibrinolytic activity to fibrinogen and fibrin. It can also inhibit factor 12 or the Hageman factor in the intrinsic blood clotting cascade.

Several small and limited studies show promising anti-inflammatory activity in post-surgical care, trauma, and chronic degenerative arthritic diseases. Its use as an atherosclerotic agent is hypothetical and has not been demonstrated in clinical studies. It has demonstrated anticoagulant and anti-platelet activity and its concomitant use with other blood thinners should be used with caution.5,6,7,8

Bromelain a proteolytic enzyme derived from the crude extract of the pineapple plant (Ananas comosus) has been reported to affect blood clotting and coagulation. The addition of bromelain reduced coagulability of both normal and hypercoagulable blood derived from animal mice models significantly resulted in 47 and 22% prolongation of PT and 20 and 10% prolongation of PTT in normal and hypercoagulable samples, respectively and inhibited adenosine diphosphate (ADP)-induced platelet aggregation by 19%. It was also noted that intra-peritoneal injection of bromelain at different concentrations showed paradoxical effects in different animal models.9

Proteolytic enzymes play an important role in human biochemistry, including the digestion of protein, but also in the role of blood coagulation and the dissolution of fibrin clots. The generation of plasmin from the zymogen plasminogen is the most common fibrinolytic enzyme. Bromelain, chymotrypsin, and trypsin are capable of digestion fibrin.10

Wobenzym is an oral enzyme combination that has been used as a systemic anti-inflammatory for a wide variety of rheumatic complaints, including osteoarthritis. Purported fibrinolytic effects have also been reported. Wobenzym is a combination of natural compounds, including 288 mg trypsin from porcine pancreas, 540 mg bromelain from pineapples (Ananas comosus) and 600 mg rutin or rutin from Japanese pagoda tree (Sophora japonica)per recommended daily dose of six tablets. The tablets are enteric coated to prevent inactivation of the enzymes during gastric passage. The tablets must be consumed on an empty stomach, separate from meals for systemic anti-inflammatory and fibrinolytic effects. No significant effects on PT and PTT times were observed in this study at the prescribed dosage.11

Strenuous and prolonged exercise such as marathon running results in a major increase in inflammatory markers, including C-reactive protein (CRP) and interleukin 6 or IL-6. IL-6 is a cytokine with a wide range of biological effects, including pro-inflammatory influences. IL-6 is a central mediator of the acute-phase response and primary determinant of hepatic production of C-reactive protein. Elevated levels of IL-6 and CRP have been found in low-grade systemic inflammation such as atherosclerosis and diabetes mellitus. In healthy men an elevated IL-6 plasma concentration has been associated with increased vascular risk and myocardial infarction. IL-6 may stimulate blood coagulation and has been suggested to be an independent predictor for sudden death. Consumption of Wobenzym before and after intense aerobic exercise significantly decreased markers associated with inflammation.12

Vitamin E has been reported to have anti-platelet activity. The effect of vitamin E was thought to be due to a slight reduction of platelet cyclooxygenase activity and inhibition of lipid peroxide formation. Vitamin E was also incorporated into platelet membranes, altered platelet shape and prevented platelet adherence to the endothelial lining, fibrin and fibronectin.13

Vitamin E has been shown to prevent LDL oxidation, inhibit the proliferation of smooth muscle cells, inhibit platelet adhesion and aggregation, inhibit the expression and function of adhesion molecules, attenuate the synthesis of leukotrienes and potentiate the release of prostacyclin through up regulating the expression of phospholipase A2 and cyclooxygenase. Collectively, these biological functions of vitamin E may account for its protection against the development of atherosclerosis.14

Omega-3 fatty acids found in marine fish oils may be incorporated into the cell membranes of platelets and endothelial cells and that they may alter the synthesis of prostaglandins. Platelet function is modestly inhibited, and platelet and vascular interactions appear to be modified in humans.15

Melatonin is an endogenous hormone that helps regulate the sleep wake cycle. Disruption of normal nighttime melatonin production has been linked to hypercoagulable states particularly in insulin-resistant diabetics. An increased thrombotic tendency in diabetes stems from platelet hyperactivity, enhanced activity of prothrombotic coagulation factors, and impaired fibrinolysis. Furthermore, a low-grade inflammatory response and increased oxidative stress accelerate the atherosclerotic process and together with an enhanced thrombotic environment, may result in premature and more severe cardiovascular disease. Current evidence suggests that melatonin inhibits platelet aggregation to some degree and might affect the coagulation cascade, altering fibrin clot structure and/or resistance to fibrinolysis.16

Aloe (Aloe vera) contains anthraquinone glycosides, aloinosides, chrysophanic acid, and salicylates and has displayed some blood-thinning properties.17

Cayenne pepper (Capsicum annuum) has been reported to inhibit platelet aggregation and blood coagulation. The researchers concluded that cayenne pepper extract in type O+ blood type exhibits antithrombotic activity and is effective in preventing blood clotting.18

Cranberry (Vaccinium myrtillus) contains flavonoids, glycosides, anthocyanins and triterpenoids and some salicylic acid.17

Feverfew (Tanacetum parthenium) contains the sesquiterpene lactone called parthenolide which has demonstrated anti-platelet activity. The purported mechanism of action of feverfew is to block the metabolism of arachidonic acid and the formation of pro-inflammatory cytokines, including thromboxanes, prostaglandins, and other leukotrienes.17

Garlic (Allium sativum) is well known for its blood thinning properties. Many ingredients in garlic have demonstrated antiplatelet and blood thinning qualities. Most ingredients of garlic, particularly alliin, have been demonstrated to inhibit the production and/or release of chemical mediators, such as platelet-activating factor (PAF), adenosine diphosphate (ADP), and thromboxanes. Some of the compounds also act as antioxidants and cause reduction of mobilization of intracellular calcium. The mechanisms for the above effects have been suggested to include inhibition and blockade of COX and fibrinogen receptors on platelet membranes by some garlic compounds. Overall, these effects are implicated to be associated with inhibition of platelet aggregation and enhancement of bleeding by different garlic preparations.17

Ginger (Zingiber officinale) contains volatile oils composed of zingiberene, bisabolene, shogaol, and gingerols which all have been reported to inhibit platelet aggregation through inhibition of thromboxane A2 synthesis. Consistent with this, it was shown in one study that a relatively high dose of ginger inhibited platelet aggregation in patients with coronary artery disease.

Ginger has been reported to inhibit platelet aggregation. Ten studies including 8 clinical trials and 2 observational studies were involved in this systematic review. Four trials showed that ginger did inhibit platelet aggregation, 4 studies did not and the observational studies were inconsistent. The authors noted that the dose of ginger was not standardized or uniform throughout the studies and the health characteristics of the subjects included in the studies varied from healthy to those with chronic disease. The researchers concluded that the platelet aggregation of ginger were equivocal and more controlled studies were needed to prove its effectiveness.19

Gingko (Gingko biloba) contain a number of bioactive compounds including flavone glycosides, kaempferol, quercetin, sesquiterpenes, and diterpenes, ginkgolides A, B, C, and M. Of the different constituents, ginkgolides, particularly ginkgolide B, have also been shown to inhibit the aggregation of platelets in vitro by inhibiting platelet activating factor (PAF) formation and binding to its receptors on platelet membranes. One study found significant inhibition of platelet aggregation in human volunteers after using ginkgolides. In another study, enhanced bleeding has been reported in patients treated with either ginkgo alone or in combination with NSAIDs.17

Gingko has been reported to inhibit blood coagulation. Preliminary studies have demonstrated that Ginkgo leaf extract can bring multiple beneficial effects for patients with cardiovascular disease or patients at high CVD risk by promoting blood circulation, decreasing blood stasis, lowering blood lipids and improving microcirculation. In vitro analysis of specific constituents isolated from Ginkgo for its ability to inhibit thrombin formation involved in the blood coagulation pathways was studied. Four biflavones and five bioflavonoids isolated from Ginkgo were found to inhibit thrombin formation. The biflavones exhibited the stronger inhibition of thrombin formation.20

Meadowsweet (Filipendula ulmaria) contains phenolic glycosides and salicylates. The presence of salicylates is associated with antiplatelet effects.17

Turmeric (Curcuma longa) contains the volatile oils zingiberene and turmerone, and curcumin. The volatile oils have antispasmodic and antibacterial actions, while curcumin produces anti-inflammatory and antiplatelet effects. In vitro experiments have demonstrated that the antiplatelet effect of curcumin and turmeric is due to inhibition of arachidonic acid metabolism and thromboxane A2 synthesis.17

White willow (Salix species) contains salicylic acid, salicin, salicortin and their derivatives, which are closely related to aspirin. It is not unexpected that the herb induces similar pharmacological effects as aspirin, including antiplatelet activity. However, there are no documented reports about white willow causing increased bleeding or interacting with NSAIDs or other blood-thinning drugs.17

Chamomile (Matricaria species) contains multiple compounds including coumarins, heniarin, flavonoids, farnesol, nerolidol, germacranolide and various glycosides. Despite the presence of coumarins, the effect of chamomile on the coagulation process has not been investigated. However, an isolated case of enhanced bleeding in a patient taking warfarin with chamomile has been reported.17

Fenugreek (Trigonella faenum-graecum) bioactive constituents include various saponins, alkaloids, and coumarins, but there are no reports that indicate that fenugreek or its coumarin constituent has effects on blood clotting when used with or without other drugs. However, the possibility of enhanced bleeding cannot be ruled out, particularly under certain circumstances, such as use of high doses in susceptible users.17

Red clover (Trifolium pratense) contains several volatile oils, including benzyl alcohol, methyl salicylate, and methyl anthranilate, isoflavonoids, cyanogenic glycosides, and coumarins. Because of the presence of coumarins, red clover has been hypothesized to increase the risk of bleeding and potentiate the effects of other blood-thinners. This possibility remains to be supported with experimental and/or clinical data.17

Dong quai (Angelica sinensis) constituents include several coumarin derivatives, such as oxypeucedan, osthole, psoralen and bergapten, and ferulic acid. The different coumarins it contains were found to prolong prothrombin time and worsen bleeding. In addition, the ferulic acid component has been shown to possess antiplatelet activities both in vivo and in vitro. The antiplatelet effect is related to inhibition of release of serotonin and adenosine diphosphate from platelets by ferulic acid. Because of its effects on blood clotting, dong quai has been implicated in enhanced bleeding with warfarin although there are no reports demonstrating its interaction with NSAIDs and other types of blood thinners.17

Evening primrose oil (Oenothera biennsis) contains different fatty acids, including the unsaturated omega-6 fatty acid gamma-linolenic acid (GLA). Gamma-linolenic acid is converted to prostaglandin E1 in vivo, which contributes, at least in part, to the claimed effects of the oil. Evening primrose oil has also been reported to reduce thromboxane production, platelet aggregation, and increased bleeding time or slow clotting time in hyperlipidemic male patients. In animal studies using rabbits, it was also found that the seed oil of the herb has both antiplatelet and anticoagulant effects. These findings suggest that evening primrose oil can enhance the chance of bleeding during or after surgery and when taken together with medications that increase bleeding or slow clotting, such as the antiplatelets aspirin, NSAIDs, and naproxen, and the anticoagulants heparin and warfarin.17

Ginseng including American ginseng (Panax quinquefolium), Korean (Panax ginseng) and Siberian (Eleutherococcus senticosus) collectively contain related compounds known as ginsenosides. In vitro studies have shown that at least some components of ginseng inhibit thromboxane A2 formation and platelet aggregation. In addition, several case studies have provided evidence of increased bleeding in association with the use of ginseng. However, the effect of ginseng on blood coagulation per se and the anticoagulant action of warfarin are not consistent.17

Flaxseed (Linum usitatissimum) seeds and oil contain fatty acids that are particularly rich in alpha-linolenic acid (ALA), an omega-3 fatty acid. ALA is believed to cause changes in the composition of platelet membrane, and this may be the reason for potentiation of the effects of anticoagulant and antiplatelet medications by flaxseed or its oil. However, this hypothesis awaits verification with experimental and/or clinical data.17

Grapefruit (Citrus paradisi) bioactive components include primarily furanocoumarins, which have been shown to inhibit various cytochromes in the liver including CYP3A4 and CYP2C9 activities irreversibly. As these enzymes are involved in the metabolism of warfarin, grapefruit products have been reported to interact with this anticoagulant drug at pharmacokinetic level.17

Green tea (Camellia sinensis) has been reported to contain some vitamin K as well as antiplatelet polyphenols. Due to the presence of vitamin K, it is implicated in counteracting the effects of anticoagulant drugs, such as warfarin, under certain conditions. The antiplatelet polyphenols in green tea, particularly catechin, have been reported to reduce or stop blood clot formation as a result of inhibition of arachidonic acid formation and thus thromboxane A2 generation in platelets.17

Oregano (Origanum vulgare) contains compounds including flavonoids primarily naringin and the essential oils, monoterpenoids and monoterpenes primarily carvacrol and thymol.

From limited observations, oregano has been suggested to have the potential to induce bleeding and exacerbate disorders of bleeding. Accordingly, at high doses, it is expected to cause greater bleeding episodes, especially in individuals with bleeding disorders and in surgery involving significant vascular damages. However, the mechanism for this effect of the herb has not been identified.17

Dietary factors and nutritional supplements can directly influence blood rheology and viscosity. An effective strategy to improve blood rheology and decrease blood viscosity would be to incorporate several of these factors and supplements into a daily regime. These strategies may be very helpful in improving longevity and preventing the occurrence of diseases caused by poor blood flow and thick blood. It goes without saying that caution should be exercised when implementing these changes if on prescription medication that affects platelets and blood coagulation. A consultation with a nutritionally oriented health professional familiar with natural blood thinners and platelet inhibitors would be wise.

“Hi, can I speak to Dr. A?”

Dr. A was a senior supervising laboratory pathologist at our local medical lab. He was also a friend who moved in some of the same social circles as I did.

“Hi, Larry, this is Dr. L. how are doing?”

After exchanging some nice pleasantries, discussing family and social engagements, I proceeded to explain to Dr. A. my theories about serum rheology and viscosity. He listened to my theories, corrected some of flawed ideas and added his specialized insight. He said that differing serum viscosities from lab samples were consistent with different levels of cholesterol, triglycerides and sugars, quantity and types of serum proteins, degrees of inflammation and ionic charges expressed by proteins and cell membranes. Yes, he agreed that keeping the blood thin in advanced age might be a good thing for most people.

References

  1. Chen H et al. Nattokinase : A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases. Biomark Insights. 2018;13:1177271918785130.
  2. Weng W et al. Nattokinase : An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease. Int J Mol Sci. 2017 Mar; (3): 523.
  3. Jang JY et al. Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation. Lab Anim Res. 2013 Dec;29(4):221-5.
  4. Kumar SS and Sabu A. Fibrinolytic Enzymes for Thromoblytic Therapy. Adv Exp Med Biol. 2019:1148:345-381. 
  5. Jadhav SW er al. Serratiopeptiase: Insight into the therapeutic applications. Biotechnol Rep (Amst). 2020 ec;28:e00544.
  6. Sharma C et al. Serratiopeptidase, A Serine Protease Anti-Inflammatory, Fibrinolytic, and Mucolytic Drug, Can Be a Usefel Adjuvant for Management of COVID-19. Front Pharmacol. 2022;12:603997.
  7. Bhagat S et al. Serratiopeptidase: a systematic review of existing evidence. Int J Surg. 2013;11(3):209-17.
  8. Kumar SS and Sabu A. Fibrinolytic Enzymes for Thromoblytic Therapy. Adv Exp Med Biol. 2019:1148:345-381. 
  9. Harmanpreet K et al. Bromelain has paradoxical effects on blood coagulability: a study using thromboelastography. Blood Coagulation & Fibrinolysis. Volume 27, Number 7, October 2016;745-752(8).
  10. Neurath H. Evolution of proteolytic enzymes. Science. 1984 Apr 27;224(4647):350-7.
  11. Bolten WW et al. The Safety and Efficacy of an Enzyme Combination in Managing Knee Osteoarthritis Pain in Adults: A Randomize, Double-Blind, Placebo-Controlled Trial.  Arthritis. 2015:251521.
  12. Grabs V et al. The effects of oral hydrolytic enzymes and flavonoids on inflammatory markers and coagulation after marathon running: study protocol for a randomized, double-blind, placebo-controlled trial. BMC Sports Sci Med Rehabil. 2014; 6: 8.
  13. Steiner M. Influence of vitamin E on platelet function in humans. J Am Coll Nutr. 1991 Oct;10(5):466-73.
  14. Chan AC. Vitamin E and atherosclerosis. J Nutr. 1998 Oct;128(10):1593-6.
  15. Goodnight Jr SH. Effects of dietary fish oil an omega-3 fatty acids on platelets and blood vessels. Semin Thromb Hemost. 1988 Jul;14(3):285-9.
  16. Otamas A et al. Diabetes and atherothrombosis: The circadian rhythm and role of melatonin in vascular protection. June 2020. https://doi.org/10.1177/1479164120920582.
  17. Abebe W. Review of herbal medications with potential to cause bleeding: dental implications, an risk prediction and prevention avenues. EPMA J. 2019 Mar;10(1):51–64.
  18. Daladdung J. The Anti-thrombotic of Cayenne Pepper (Capsicum annuum) in Type O+ Human Blood Coagulation. Ascendens Asia Journal of Multidisciplinary Research Abstracts. 2019. Vol 3. No 2.
  19. Marx W et al. The Effect of Ginger (Zingiber officinale) on Platelet Aggregation: A Systematic Literature Review. PLos One. 2015;10(10):e0141119.
  20. Chen TR et al. Biflavones from Ginkgo biloba as inhibitors of human thrombin. Biorganic Chemistry. 2019 November. Vol 92. 103199.

Published on April 20, 2024

About the Author

Douglas G. Lobay, ND, is a practicing naturopathic physician in Kelowna, British Columbia. Dr. Lobay graduated with a Bachelor of Science degree from the University of British Columbia in 1987. He then attended Bastyr College of Health Sciences in Seattle, Washington, and graduated with a Doctor of Naturopathic Medicine in 1991. While attending Bastyr College, he began to research the scientific basis of natural medicine. He was surprised to find that many of the current medical journals abounded with scientific information on the use of diet, nutrition, vitamins, and botanical medicines. Besides practicing naturopathic medicine Dr. Lobay enjoys research, writing and teaching others about the virtues of good health and nutrition. He has authored several books, numerous articles, and papers and has taught many courses at seminars and colleges throughout his career. He is married to Natalie and has two daughters, Rachel and Jessica. He also enjoys hiking, hockey, skiing, tennis, travelling and playing his guitar.